Fluvoxamine pharmacokinetics

Fluvoxamine Pharmacokinetic—CYP1A2 inhibition TCAs Clozapine Theophylline... 

Spigset O, Granberg K, Hagg S, et al. Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms. Eur J Clin Pharmacol 1997 52(2) 129-33. 

Smoking does not appear to alter citalopram pharmacokinetics, and has onfy modest effects on fluvoxamine pharmacokinetics. 

Spigset O, Carleboig L, Hedenmalm K, Dahlqvist R. Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Chn Pharmacol Ther (1995) 58,399-403. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

Franchini L, Serretti A, Gasperini M, Smeraldi E (1998) Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res 32 255-259 Fukuda T, Nishida Y, Zhou Q, Yamamoto I, Kondo S, Azuma J (2000) The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Fur J Clin Pharmacol 56 175-180... 

Wagner, W. and Vause, E.W. (1995) Fluvoxamine. A review of global drug-drug interaction data. Clin Pharmacokinet 29 Suppl 1 26-31. 

As of the date of this chapter (circa March, 2002), labeling changes regarding pediatric use have resulted from only two programs—the study of buspirone in pediatric GAD and a pharmacokinetic study of fluvoxamine in pediatric OCD (fluvoxamine already had a controlled clinical trial in pediatric patients). Two placebo-controlled trials with buspirone in pediatric GAD did not reveal a treatment effect, and this negative outcome is reflected in Buspar labeling. A pharmacokinetic study of fluvoxamine dosed at 100 mg bid in pediatric... 

Benca RM, Obermeyer WH, Thisted RA, et al Sleep and psychiatric disorders a metaanalysis. Arch Gen Psychiatry 49 651-668, 1992 Benfield P, Ward A Fluvoxamine a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in depressive illness. Drugs 32 313-334, 1986... 

Claassen V Review of the pharmacology and pharmacokinetics of fluvoxamine. Br J Pharmacol 15 [suppl 3) 349S-355S, 1983... 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

Although there is no age-related change in fluvoxamine plasma levels, fluvoxamine has nonlinear and sex-dependent pharmacokinetics ( 304). A doubling of the dose from 50 to 100 mg twice a day causes, on average, a 340% increase in fluvoxamine plasma levels, which is more pronounced in men (460%) than in women (240%). 

In comparison with TCAs, SSRIs cause fewer pharmacodynamic drug-drug interactions but some (i.e., fluvoxamine, fluoxetine, paroxetine) cause more CYP enzyme mediated pharmacokinetic drug-drug interactions. Unlike TCAs, SSRIs do not potentiate alcohol and perhaps even slightly antagonize its acute CNS effects. Nevertheless, there are some important adverse interactions. 

Hartter S, Wetzel H, Hammes E, et al. Nonlinear pharmacokinetics of fluvoxamine and gender differences. TherDrug Monii 1998 20 446-449. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

Lam, Y.W., Alfaro, C.L., Ereshefsky, L., and Miller, M., Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone, J. Clin. Pharmacol, 43(11), 1274-1282, 2003. 

The effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride have been studied in a randomized, double-blind, crossover study in 12 healthy volunteers who took fluconazole 200 mg/day (400 mg on day 1), fluvoxamine 100 mg/day,... 

SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 out-patients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (97). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. 

The effects of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone have been investigated in 10 healthy volunteers. Fluvoxamine moderately increased plasma buspirone concentrations and reduced the production of the active metabolite of buspirone. The mechanism of this interaction is probably inhibition of CYP3A4. However, this pharmacokinetic interaction was not associated with impaired psychomotor performance and is probably of limited clinical significance (33). 

Fluvoxamine increases clozapine plasma concentrations (34,35). In 16 patients taking clozapine monotherapy, fluvoxamine 50 mg was added in the hope of ameliorating the negative symptoms of schizophrenia (36). At steady state the serum concentrations of clozapine and its metabolites increased up to five-fold (average two- to three-fold). However, adverse effects were almost unchanged in frequency and severity, in spite of the pharmacokinetic interaction. 

Sexual dysfunction is a common adverse effect of SSRIs and various treatments have been proposed, of which sildenafil is the only strategy with consistent support from controlled trials. Sildenafil is metabolized by CYP3A4, which is inhibited by fluvoxamine. The effects of fluvoxamine (100 mg/day for 10 days) on the pharmacokinetics of sildenafil (50 mg orally) has been evaluated in 12 healthy men (mean age 25 years) using a doubleblind, placebo-controlled, crossover design (46). Fluvoxamine increased the AUC of sildenafil by about... 

Neuvonen PJ. The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone. Eur J Clin Pharmacol 1998 54(9-10) 761-6. 

Kusumoto M, Ueno K, Oda A, Takeda K, Mashimo K, Takaya K, Fujimura Y, Nishihori T, Tanaka K. Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men. Clin Pharmacol Ther 2001 69(3) 104-7. 

Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JA, Berecz R, Duran M, Benitez J. Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients. J Clin Psychopharmacol 1999 19(6) 494-9. 

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